The effect of the stable prostacyclin analogue ZK 36374 on experimental coronary thrombosis in the pig

Giessen, Willem J. van der; Mooi, Wolter J.; Rutteman, A. M.; Berk, Luuk; Verdouw, Pieter D.

doi:10.1016/0049-3848(84)90375-x

Cited by 14 publications

(2 citation statements)

References 7 publications

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“…Alternatively, the mechanism of action of heparin in inhibiting LPS-induced platelet recruitment may be due to other effects of this molecule, for example, on the vascular endothelium (Paul et al, 1984), or as a free radical scavenger (McClain & Brestel, 1982). The prostacyclin analogue, ZK 36374, is known to inhibit platelet activation in vivo in other circumstances (Van der Giessen et al, 1984) and its action in these experiments suggests that our observations are consistent with the concept that the increase in thoracic platelet numbers reflects platelet activation rather than changes in pulmonary blood flow, a conclusion confirmed by the failure of LPS to induce significant accumulation of radiolabelled erythrocytes.…”

Section: Discussionmentioning

confidence: 99%

The involvement of platelet activating factor in endotoxin‐induced pulmonary platelet recruitment in the guinea‐pig

Beijer

Botting

Crook

et al. 1987

British J Pharmacology

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1 Exposure of conscious guinea-pigs to an aerosol of endotoxin (25-100ug ml-') resulted in a doserelated, progressive accumulation of platelets in the thoracic region. Accumulation of" 'indium oxine labelled erythrocytes was not observed following exposure to an aerosol of endotoxin (50 fig ml-'). 2 Pretreatment of guinea-pigs with the selective platelet activating factor (Paf)-antagonists. CV-3988 or brotizolam resulted in a dose-related inhibition of endotoxin-induced pulmonary platelet recruitment. Pretreatment of guinea-pigs with the selective Paf-antagonist BN 52021 resulted in significant inhibition of endotoxin-induced pulmonary platelet recruitment, although the effects of BN 52021 were not dose-related. 3 Pretreatment of guinea-pigs with indomethacin at doses known to inhibit cyclo-oxygenase did not inhibit endotoxin-induced pulmonary platelet recruitment, whereas higher doses of indomethacin produced a reduction in platelet recruitment in the lung. 4 Pretreatment of guinea-pigs with the anticoagulant heparin and the prostacyclin analogue ZK 36374 inhibited endotoxin-induced platelet recruitment. 5 These observations suggest that endotoxin-induced pulmonary platelet recruitment in the guineapig is secondary to the release of platelet activating factor, but not to cyclo-oxygenase products of arachidonic acid and may also involve activation of the coagulation cascade.

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Section: Discussionmentioning

confidence: 99%

The involvement of platelet activating factor in endotoxin‐induced pulmonary platelet recruitment in the guinea‐pig

Beijer

Botting

Crook

et al. 1987

British J Pharmacology

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“…Iloprost (initially called ZK36374) is a carbacy clin analogue of PGI2 which has been evalu ated both in experimental animals [19][20][21][22] and in healthy human volunteers [23,24]. Preliminary results suggest that Iloprost is less potent than PGU in lowering blood pres sure [20][21][22][23][24] but equipotent to PGI2 as an antithrombotic agent [20], This dissociation between blood pressure lowering and anti thrombotic actions of Iloprost may be ex ploited clinically in situations where a fall in blood pressure is undesirable.…”

Section: Introductionmentioning

confidence: 99%

Comparison of Inhibitory Actions of Prostacyclin and a New Prostacyclin Analogue on the Aggregation of Human Platelet in Whole Blood

Saniabadi¹,

Belch²,

Lowe³

et al. 1987

Pathophysiol Haemos Thromb

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Prostacyclin (PGI₂), an unstable endogenous prostanoid, is a potent vasodilator and inhibitor of platelet aggregation. The use of exogenous PGI₂ as an antithrombotic agent is limited by its chemical instability and lack of dissociation between its vasodilatory and antithrombotic actions. Iloprost (ZK36374) is a recently developed, chemically stable, carbacyclin analogue of PGI₂. Preliminary evaluation studies have shown a significant dissociation between vasodilatory and antithrombotic actions of Iloprost. We have compared the effects of PGI₂ and Iloprost on platelet aggregation in human whole blood. Platelet aggregation was induced by ADP (4 μM), adrenaline (Adr, 0.4 μM) and arachidonic acid (AA, 0.4 mM). Aggregation was quantified as a fall in the number of single platelets counted using the Clay Adams Ultra Flo 100 whole blood platelet counter. In the absence of any PGI₂ or Iloprost, each aggregating agent induced up to an 80% fall in the number of single platelets counted. When blood was pre-incubated with PGI₂ (1–6 nM) or Iloprost (1–6 nM), aggregation responses to all three aggregating agents were inhibited in a dose-dependent manner. Iloprost was equipotent to PGI₂ against ADP-induced aggregation but was more potent than PGI₂ against Adr- and AA-induced aggregation. It is concluded that Iloprost, as a chemically stable PGI₂ analogue, may be superior to PGI₂ as an antithrombotic agent.

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Coronary thrombolysis with and without nifedipine in pigs

et al. 1988

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To investigate whether addition of Ca2+ antagonists adds to the beneficial effects of thrombolysis we studied recovery of regional myocardial performance in pigs, in which occlusive thrombi were induced by electrical stimulation, with and without addition of nifedipine to the thrombolytic agent. To this end, four different groups of animals with thrombotic coronary occlusion were studied. Groups 1 and 2 received either saline or intracoronary nifedipine (0.1 micrograms.kg-1.min-1) 15 min after coronary artery occlusion. Groups 3 and 4 were treated with the thrombolytic agent plasmin which was infused directly into the left anterior descending coronary artery (LADCA) at a rate of 2 U.min-1. The animals in group 4 also received intracoronary nifedipine. 4 h after thrombus formation the animals were sacrificed. No important differences in systemic hemodynamics were observed between the four groups of animals. Reperfusion occurred only in the animals which received plasmin, with or without nifedipine. After intracoronary plasmin regional blood flow increased from 7 +/- 2 to 40 +/- 7 ml.min-1.100 g-1 in the LADCA-perfused subepicardial and from 9 +/- 2 to 30 +/- 6 ml.min-1.100 g-1 in the LADCA-perfused subendocardial layers. The combination of plasmin and nifedipine increased flow to the LADCA-perfused subepicardial layers from 8 +/- 2 to 74 +/- 21 ml.min-1.100 g-1 and that to the subendocardial layers from 8 +/- 2 to 57 +/- 16 ml.min-1.100 g-1 (in both cases: p less than 0.05 vs. plasmin alone). However, addition of nifedipine did not enhance recovery of regional myocardial function or high-energy phosphate metabolism. Because reperfusion was accompanied by a high ventricular ectopic activity, the question may be raised of whether reperfusion of ischemic myocardium which does not result in functional recovery could be deleterious.

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The effect of the stable prostacyclin analogue ZK 36374 on experimental coronary thrombosis in the pig

Cited by 14 publications

References 7 publications

The involvement of platelet activating factor in endotoxin‐induced pulmonary platelet recruitment in the guinea‐pig

The involvement of platelet activating factor in endotoxin‐induced pulmonary platelet recruitment in the guinea‐pig

Comparison of Inhibitory Actions of Prostacyclin and a New Prostacyclin Analogue on the Aggregation of Human Platelet in Whole Blood

Coronary thrombolysis with and without nifedipine in pigs

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